Using Cytomegalovirus to Modulate Tumor-Associated Macrophages and Drive Antitumor Immune Responses
Abstract
Melanoma is the most-deadly skin cancer and military personnel are at elevated risk for developing melanoma, largely because of deployments to regions with intense sun exposure. In many cases, these regions also require treatment with drugs to prevent malaria, which can make these soldiers more likely to get sunburns, thus potential increasing their risk for future skin cancers. Ten years ago, having melanoma that escaped the primary site of tumor development was usually a death-sentence. However, new therapies targeting the immune system have been curing such metastatic melanoma. Unfortunately, only a fraction of patients achieve these cures. Therefore, it is critical to identify barriers to the success of immune therapies and define how these barriers can be targeted. One cell type that may inhibit immune responses within tumor are called “Tumor-Associated Myeloid cells, or “TAMs.” Over the last few years, it has become increasingly clear that TAMs can block immune responses within tumors. However, it is not clear how TAMs can be or should be targeted. Our lab uses a common virus called cytomegalovirus (CMV) to promote immune responses within melanoma. CMV is a member of the herpes family of viruses, and it infects most people in the world without causing disease. However, CMV has one important feature that forms the basis of the current proposal: it has evolved mechanisms to attract and infect myeloid cells for its own ends. We have discovered that CMV-encoded molecules alter the TAM population within tumors and that CMV infection of these TAMs drives productive immune responses. Moreover, we have begun to tease apart the molecular mechanisms responsible for this effect, which will enable approaches to selectively target the most important pathways. Most significantly, CMV infection of TAMs converted tumors that were resistant to immune therapy into tumors that could be cleared by the immune response. Overall, this proposal has two specific aims: (1) We will determine how the virus and the host response to the virus combine to modulate TAMs, with the overarching goal of defining critical pathways that must be targeted to engage productive immune responses in the tumor. (2) Because CMV attracts and infects myeloid cells, we will determine whether this virus can be used to selectively target genes expressed by TAMs to alter their behavior in a precise manner. Overall, these aims will address the MRP challenge to redefine prevention by targeting a significant barrier to immune therapy, with the long-term goal of enabling immune therapies to both clear tumor cells and prevent recurrence or metastatic growth at distant sites. The proposed experiments will lay the foundation for precise and selective targeting of TAMs and establish novel tools for mechanistic and translational research.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010840
Entities
People
- Christopher M Snyder
Organizations
- Thomas Jefferson University
- United States Army